Polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome (PMSE) is a severe neurodevelopmental disorder characterized by autism, intractable epilepsy, and a high rate of childhood mortality, recently identified in the Old Order Mennonite community of Lancaster County, PA. PMSE results from a homozygous deletion of the STRADa gene, encoding the protein STRADa, which serves as an upstream regulator of the mammalian target of rapamycin (mTOR) pathway. Loss of mTOR inhibition is correlated with several more common neurodevelopmental disorders, including Tuberous Sclerosis Complex (TSC) and Focal Cortical Dysplasia (FCD). Immunohistochemical analysis of PMSE post-mortem brain tissue reveals evidence of mTOR hyperactivity and failed neuronal migration, suggesting a possible common pathogenic mechanism. Therefore, STRADa was introduced as a key mTOR regulator critical for normal brain development. However, the mechanism by which it mediates this process is not understood. This proposal aims to define the role of STRADa in neuronal migration and cortical development, and thereby identify pharmacological targets for mTOR-associated neurodevelopmental disorders. Only a single PMSE post-mortem specimen has been available for analysis, and no STRADa knockout (KO) models currently exist. As a consequence, the cause of PMSE-associated neuropathology remains yet unknown. The proposed research will generate a novel STRADa KO mouse strain as a key tool for defining STRADa's function. The focus of Aim 1 is to characterize brain development in the STRADa KO mouse and identify the extent to which aberrant neuronal migration is dependent upon mTOR signaling. The focus of Aim 2 is to define in vitro the mechanism by which STRADa mediates neuronal migration using a novel neural progenitor cell migration assay. Cumulatively, the proposed experiments will identify STRAD as a critical regulator of mammalian cortical development. PUBLIC HEALTH RELEVANCE: Many patients with intractable epilepsy and autism suffer from neurological disorders associated with hyperactive mTOR signaling during development. Investigating STRAD, as a critical regulator of mTOR, will reveal not only the mechanism by which this protein and signaling pathway control normal brain development, but also novel therapeutic targets for treating patients with otherwise intractable symptoms.